Fluoxetine exposure in adolescent and adult female mice decreases cocaine and sucrose preference later in life

Abstract

Background: Preclinical evidence from male subjects indicates that exposure to psychotropic medications, during early development, results in long-lasting altered responses to reward-related stimuli. However, it is not known if exposure to the antidepressant fluoxetine, in female subjects specifically, changes sensitivity to natural and drug rewards, later in life.

Aims: The aim of this work was to investigate if exposure to fluoxetine mediates enduring changes in sensitivity to the rewarding properties of cocaine and sucrose, using female mice as a model system.

Methods: We exposed C57BL/6 female mice to fluoxetine (250 mg/L in their drinking water) for 15 consecutive days, either during adolescence (postnatal day 35-49) or adulthood (postnatal day 70-84). Twenty-one days later, mice were examined on their behavioral reactivity to cocaine (0, 2.5, 5, 7.5 mg/kg) using the conditioned place preference paradigm, or assessed on the two-bottle sucrose (1%) test.

Results: We found that regardless of age of antidepressant exposure, female mice pre-exposed to fluoxetine displayed reliable conditioning to the cocaine-paired compartment. However, when compared to respective age-matched controls, antidepressant pre-exposure decreased the magnitude of conditioning at the 5 and 7.5 mg/kg cocaine doses. Furthermore, fluoxetine pre-exposure reduced sucrose preference without altering total liquid intake.

Conclusions: The data suggest that pre-exposure to fluoxetine, during adolescence or adulthood, results in a prolonged decrease in sensitivity to the rewarding properties of both natural and drug rewards in female C57BL/6 mice.

Keywords: Anhedonia; C57BL/6; conditioned place preference; juvenile; reward; selective serotonin reuptake inhibitor.

Figure 1.

Experimental design. Separate groups of adolescent (postnatal day (PD)-35) and adult (PD70) female C57BL/6 mice received vehicle (VEH) or fluoxetine (FLX; 250 mg/mL, in their drinking water) for 15 consecutive days. Twenty-one days later, mice were tested on their preference for cocaine (0, 2.5, 5, or 7.5 mg/kg) using the place conditioning test, or sucrose (1%) preference using the two-bottle choice test. Specifically, (a) adolescent FLX pretreated animals initiated behavioral testing at PD70, while (b) adult FLX pre-exposed mice initiated behavioral testing at PD105.

Figure 2.

Effects of adolescent fluoxetine (FLX) exposure on body weight gain and the tail suspension test. (a) Body weight increased across days of treatment (postnatal day (PD) 35–49), regardless of FLX or water-control (CON) conditions. However, when compared to CON mice, FLX-exposed mice displayed lower weight gain as of the second day (PD36) of antidepressant exposure (p<0.05). Twenty-one days later (PD70), no differences in body weight were noted between the groups (p>0.05; inset). Data are presented as average weight across days and antidepressant exposure (mean ± standard error of the mean (SEM), in g). (b) Twenty-four hours post antidepressant exposure (PD50), a separate group of adolescent mice was tested in the tail suspension test. FLX-exposed mice displayed higher time (s) to adopt a posture of immobility, (c) as well as a lower time spent immobile, when compared to CON mice (p<0.05). Data are presented as total time in seconds (mean ± SEM). *Significantly different when compared to CON (p<0.05).

Figure 3.

Effects of adolescent fluoxetine (FLX) exposure on reward-related behavior in adulthood. (a) Three-weeks after adolescent antidepressant exposure (postnatal day (PD)-70+), FLX-pretreated mice displayed decreased sensitivity to 5 and 7.5 mg/kg cocaine, when compared to water-pretreated control (CON) mice receiving the same doses of cocaine (n=9–11 per experimental group; p<0.05). *Within cocaine-dose group comparison (p<0.05). αSignificantly different when compared to age-matched controls conditioned to saline (p<0.05). (b) Adolescent FLX pretreatment reduced preference for a 1% sucrose solution three weeks after antidepressant exposure (n=12 per group; p<0.05). (c) No differences in total liquid intake were observed between the experimental groups (p>0.05).

Figure 4.

Effects of adult fluoxetine (FLX) exposure on body weight gain and the tail suspension test. (a) Body weight increased across days of treatment (postnatal day (PD) 70–84), regardless of FLX or water-control (CON) conditions. However, when compared to CON mice, FLX-exposed mice displayed lower weight gain as of the second day of antidepressant exposure (PD71), remaining lower until PD78 (p<0.05). Twenty-one days post FLX exposure (PD105) no differences in body weight were noted between the groups (p>0.05; inset). Data are presented as average weight across days and antidepressant exposure (mean ± standard error of the mean (SEM), in g). (b) Twenty-four hours post antidepressant exposure (PD85), a separate group of adult mice was tested in the tail suspension test. FLX-exposed mice displayed higher time (s) to adopt a posture of immobility, (c) as well as a lower time spent immobile, when compared to CON mice (p<0.05). Data are presented as total time in seconds (mean ± SEM). *Significantly different when compared to CON (p<0.05).

Figure 5.

Enduring effects of adult fluoxetine (FLX) exposure on reward-related behavior. (a) Three-weeks after adult antidepressant exposure, FLX-pretreated mice displayed decreased sensitivity to 5 and 7.5 mg/kg cocaine, when compared to water-pretreated control (CON) mice exposed to the same doses of cocaine (n=10 per experimental group; p<0.05). *Within cocaine group comparison (p<0.05). αSignificantly different when compared to age-matched controls conditioned to saline (p<0.05). (b) Adult FLX pretreatment reduced preference for a 1% sucrose solution three weeks after antidepressant exposure (n=12 per group; p<0.05). (c) No differences in total liquid intake were observed between the experimental groups (p>0.05).

Figure 6.

Enduring effects of fluoxetine (FLX) exposure on general locomotor activity. Three-weeks after (a) adolescent (postnatal day (PD)-70; or (b) adult (PD105) antidepressant treatment, no differences in distance traveled (cm) were noted between the groups (p>0.05). Data shown as mean ± standard error of the mean (SEM).